101 research outputs found
Ephs and ephrins in adult endothelial biology
Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.Nephrolog
EPH receptor B2 stimulates human monocyte adhesion and migration independently of its EphrinB ligands
The molecular basis of atherosclerosis is not fully understood and mice studies have shown that Ephrins and EPH receptors play a role in the atherosclerotic process. We set out to assess the role for monocytic EPHB2 and its Ephrin ligands in human atherosclerosis and show a role for EPHB2 in monocyte functions independently of its EphrinB ligands. Immunohistochemical staining of human aortic sections at different stages of atherosclerosis showed that EPHB2 and its ligand EphrinB are expressed in atherosclerotic plaques and that expression proportionally increases with plaque severity. Functionally, stimulation with EPHB2 did not affect endothelial barrier function, nor did stimulation with EphrinB1 or EphrinB2 affect monocyte-endothelial interactions. In contrast, reduced expression of EPHB2 in monocytes resulted in decreased monocyte adhesion to endothelial cells and a decrease in monocyte transmigration, mediated by an altered morphology and a decreased ability to phosphorylate FAK. Our results suggest that EPHB2 expression in monocytes results in monocyte accumulation by virtue of an increase of transendothelial migration, which can subsequently contribute to atherosclerotic plaque progression.Nephrolog
Transcatheter heart valve selection and permanent pacemaker implantation in patients with pre-existent right bundle branch block
Background-Right bundle branch block is an established predictor for new conduction disturbances and need for a permanent pacemaker (PPM) after transcatheter aortic valve replacement. The aim of the study was to evaluate the absolute rates of transcatheter aortic valve replacement related PPM implantations in patients with pre-existent right bundle branch block and categorize for different transcatheter heart valves. Methods and Results-We pooled data on 306 transcatheter aortic valve replacement patients from 4 high-volume centers in Europe and selected those with right bundle branch block at baseline without a previously implanted PPM. Logistic regression was used to evaluate whether PPM rate differed among transcatheter heart valves after adjustment for confounders. Mean age was 83±7 years and 63% were male. Median Society of Thoracic Surgeons score was 6.3 (interquartile range, 4.1-10.2). The following transcatheter valve designs were used: Medtronic CoreValve (n=130; Medtronic, Minneapolis, MN); Edwards Sapien XT (ES-XT; n=124) and Edwards Sapien 3 (ES-3; n=32; Edwards Lifesciences, Irvine, CA); and Boston Scientific Lotus (n=20; Boston Scientific Corporation, Marlborough, MA). Overall permanent pacemaker implantation rate post-transcatheter aortic valve replacement was 41%, and per valve design: 75% with Lotus, 46% with CoreValve, 32% with ES-XT, and 34% with ES-3. The indication for PPM implantation was total atrioventricular block in 98% of the cases. Lotus was associated with a higher PPM rate than all other valves. PPM rate did not differ between ES-XT and ES-3. Ventricular paced rhythm at 30-day and 1-year follow-up was present in 81% at 89%, respectively. Conclusions-Right bundle branch block at baseline is associated with a high incidence of PPM implantation for all transcatheter heart valves. PPM rate was highest for Lotus and lowest for ES-XT and ES-3. Pacemaker dependency remained high during followup
Fulminant cerebral edema as a lethal manifestation of COVID-19
The contribution of neurological symptomatology to morbidity and mortality after infection with Severe Acute Respiratory Syndrome-associated Coronavirus (SARS CoV II) is ill-defined. We hereby present a case of a 57-year old male patient, in excellent physical condition, who was admitted to the Intensive Care Unit (ICU), with respiratory distress duo to SARS Co
Downregulation of endothelial plexin A4 under inflammatory conditions impairs vascular integrity
Objective: Besides hyperlipidemia, inflammation is an important determinant in the initiation and the progression of atherosclerosis. As Neuroimmune Guidance Cues (NGCs) are emerging as regulators of atherosclerosis, we set out to investigate the expression and function of inflammation-regulated NGCs.Methods and results: NGC expression in human monocytes and endothelial cells was assessed using a publicly available RNA dataset. Next, the mRNA levels of expressed NGCs were analyzed in primary human monocytes and endothelial cells after stimulation with IL1 beta or TNF alpha. Upon stimulation a total of 14 and 19 NGCs in monocytes and endothelial cells, respectively, were differentially expressed. Since plexin A4 (PLXNA4) was strongly downregulated in endothelial cells under inflammatory conditions, the role of PLXNA4 in endothelial function was investigated. Knockdown of PLXNA4 in endothelial cells markedly impaired the integrity of the monolayer leading to more elongated cells with an inflammatory phenotype. In addition, these cells showed an increase in actin stress fibers and decreased cell-cell junctions. Functional assays revealed decreased barrier function and capillary network formation of the endothelial cells, while vascular leakage and trans-endothelial migration of monocytes was increased.Conclusion: The current study demonstrates that pro-inflammatory conditions result in differential expression of NGCs in endothelial cells and monocytes, both culprit cell types in atherosclerosis. Specifically, endothelial PLXNA4 is reduced upon inflammation, while PLXNA4 maintains endothelial barrier function thereby preventing vascular leakage of fluids as well as cells. Taken together, PLXNA4 may well have a causal role in atherogenesis that deserves further investigation.Nephrolog
Outcome measures in Angelman syndrome
Background: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children’s functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. Aim: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. Methods: The study sample consisted of 28 children with AS aged 2–18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. Results: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). Conclusions: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. Trial registration: Registered d.d. 23-04-2020 under number ‘NL8550’ in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075</p
Outcome measures in Angelman syndrome
Background: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children’s functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. Aim: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. Methods: The study sample consisted of 28 children with AS aged 2–18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. Results: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). Conclusions: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. Trial registration: Registered d.d. 23-04-2020 under number ‘NL8550’ in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075</p
A mathematical framework for critical transitions: normal forms, variance and applications
Critical transitions occur in a wide variety of applications including
mathematical biology, climate change, human physiology and economics. Therefore
it is highly desirable to find early-warning signs. We show that it is possible
to classify critical transitions by using bifurcation theory and normal forms
in the singular limit. Based on this elementary classification, we analyze
stochastic fluctuations and calculate scaling laws of the variance of
stochastic sample paths near critical transitions for fast subsystem
bifurcations up to codimension two. The theory is applied to several models:
the Stommel-Cessi box model for the thermohaline circulation from geoscience,
an epidemic-spreading model on an adaptive network, an activator-inhibitor
switch from systems biology, a predator-prey system from ecology and to the
Euler buckling problem from classical mechanics. For the Stommel-Cessi model we
compare different detrending techniques to calculate early-warning signs. In
the epidemics model we show that link densities could be better variables for
prediction than population densities. The activator-inhibitor switch
demonstrates effects in three time-scale systems and points out that excitable
cells and molecular units have information for subthreshold prediction. In the
predator-prey model explosive population growth near a codimension two
bifurcation is investigated and we show that early-warnings from normal forms
can be misleading in this context. In the biomechanical model we demonstrate
that early-warning signs for buckling depend crucially on the control strategy
near the instability which illustrates the effect of multiplicative noise.Comment: minor corrections to previous versio
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